Therapeutic drug discovery for CDKL5 deficiency using random shRNA selection

PI: Robert Wilson, MD, PhD

Institution: Children's Hospital of Philadelphia

CDKL5 deficiency causes an early-onset variant of Rett Syndrome and is associated with severe learning difficulties and seizures. CDKL5 is important for the development and function of neurons. Although more highly expressed in neurons, CDKL5 is ubiquitously expressed and is apparently multifunctional. The exact functions of CDKL5, and the targets and downstream signaling pathways it impacts, are not yet fully elucidated. There are currently no approved treatments for CDKL5 deficiency. We have developed a novel technology, based on very small RNA molecules called shRNAs, that allows us to screen up to 3 million bioactive molecules in a single dish using cell-culture disease models. Our screening is based on improved cell function and is unbiased: after introduction of random shRNAs into cells, we let the cells tell us which shRNAs work best. Hit shRNAs can be optimized by creating variants and re-screening. Bioinformatic analyses of hit shRNAs reveal relevant biochemical pathways, potential drug target pathways, and potential therapeutics. For this project we will apply our approach to screening to cell-culture models of CDKL5 deficiency. The overall goal is to identify drugs and drug-target pathways for the treatment of CDKL5 deficiency.

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